Cerebral ischemia is the reduction in blood flow to levels that are insufficient to maintain the metabolism necessary for normal function and structure of the brain. When the blood supply decreases, the supply of oxygen, nutrients and the elimination of products from the metabolism of a biological tissue also decreases, all of which produces damages in the brain tissue.
Cerebral ischemia may be total or partial, depending on whether it affects all the brain or just one or several areas. Frequent causes of total cerebral ischemia are the decrease in cardiac output (cardiac arrest or arrhythmias) and the decrease in peripheral resistance (systemic shock, cardiovascular surgery or hypotension during anaesthesia due to general surgery). The most frequent cause of partial cerebral ischemia is a brain stroke.
A brain stroke is a cerebral circulation disorder which causes a transient or definitive alteration of the functioning of one or several parts of the brain. According to its aetiology, the brain stroke may be ischemic or haemorrhagic. An ischemic stroke arises when the brain loses blood supply due to the sudden and immediate interruption of blood flow, which frequently occurs due to the occlusion of any of the arteries that supply the brain matter because of a blood clot. In contrast, the haemorrhagic stroke is triggered by the rupture of an encephalic blood vessel due to a hypertensive peak, a congenital aneurism, or other less frequent causes.
The affectation of specific areas of the brain by brain strokes generates focalized manifestations such as paralysis or plegia of a hemibody (one half of the body), facial paralysis, aphasia (loss of the capacity to produce or understand language) and disorientation, among others. In general, the symptoms of strokes are variables depending on the brain area affected. In milder cases, the consequences may go unnoticed and may not be greatly limiting for the patient due to the anodyne nature of the symptoms. However, strokes frequently cause permanent neuronal damage or result in the death of the individual. Indeed, brain stroke is one of the main causes of mortality and of permanent incapacity in adults in the majority of developed countries.
As previously commented, the damages caused by cerebral ischemia after a stroke are related to the malfunctioning of brain tissue and its possible death due to lack of energy. To re-establish the energy supply after an ischemic episode it is, therefore, necessary to re-establish the blood supply in the affected area.
To date, the only pharmacological treatment approved for the treatment of strokes is tissue plasminogen activator (tPA) by intravenous route. tPA has a thrombolytic effect, i.e. it produces the disintegration of the clot which causes the lack of blood supply in the brain area at risk. Therefore, this treatment is only indicated for ischemic stroke patients, its use being counterproductive in haemorrhagic stroke patients. Another way of re-establishing blood flow is by a surgical intervention that eliminates the occlusion.
Whatever the treatment, it is important that it is promptly carried out in order to avoid major damages in the tissue caused by cerebral ischemia. The administration of tPA is only indicated if it is performed during the first 4.5 hours after the start of symptoms, although it could also be effective some hours later in those cases where there is still recoverable tissue. This means that the therapeutic window of the thrombolytic treatment available is very small. Furthermore, although the re-establishing of the blood flow (process known as reperfusion) puts an end to the situation of ischemia, it entails new damages in the brain tissue (damages due to reperfusion).
The damages due to reperfusion are due to the inflammatory response of the tissues affected by ischemia and, very particularly, to the induction of oxidative stress caused by the sudden availability of oxygen. These damages significantly contribute to the detriment in the stroke patient's health. Despite the fact that great efforts are being made that permit minimizing the damages caused by ischemia and reperfusion, to date there are no effective strategies for this.
An area of research to limit the negative effects of reperfusion is therapeutic hypothermia. Hypothermia can help to moderate the intracranial pressure and, therefore, reduce the harmful effects of the patient's inflammatory immune response and the production of free radicals during reperfusion. However, this therapy is complex in its application and its effects are limited.
Some studies suggest the use of iron chelating agents to avoid damages due to reperfusion. During reperfusion, the iron transported by the blood is capable of catalysing reactions that produce reactive oxygen species, mainly hydroxyl radicals. These radicals, in turn, start the peroxidation of the lipids, cause the degradation of the DNA and inactivate enzymes. Due to its high lipid content, the brain is especially sensitive to peroxidation, which causes considerable damages during reperfusion. International patent application WO2006/20727 proposes the use of deferoxamine as neuroprotector agent against the harmful effects of reperfusion. However, the administration of deferoxamine poses problems due to its reduced half-life in plasma and because its intravenous injection may cause hypotension with the risk of lethal shock, so that it is only effective when administered by intranasal route in the upper part of the nasal cavity.
Thus, it would be desirable to find new strategies for treating brain strokes.